Therapeutic agents are administered to animals by a variety of routes. These routes include, for example, oral ingestion, topical application or parental administration. The particular route selected by the practitioner depends upon factors such as the physiochemical properties of the pharmaceutical or therapeutic agent, the condition of the host, and economic factors.
For example, one method of formulating a therapeutic agent for oral, topical, dermal or subdermal administration is to formulate the therapeutic agent as a paste or as an injectable formulation and reference is made to U.S. application Ser. No. 09/504,741, filed Feb. 16, 2000, now pending, entitled IMPROVED PASTE FORMULATIONS or to Ser. No. 09/346,905, filed Jul. 2, 1999, now pending; Ser. No. 09/112,690, filed Jul. 9, 1999, now allowed; and Ser. No. 09/15,277, filed Sep. 14, 1998, now pending, entitled LONG ACTING INJECTABLE FORMULATIONS CONTAINING HYDROGENATED CASTOR OIL, or U.S. application Ser. No. 10/177,822, entitled ANTHELMINTIC ORAL HOMOGENEOUS VETERINARY PASTES, filed Jun. 21, 2002, now pending. Alternatively, it is possible that therapeutic agents may be administered topically as, for example, as spot-on or pour-on formulations and reference is made to U.S. Pat. No. 6,426,333, issued Jul. 30, 2002 and to co-pending application Ser. No. 09/271,470, filed on Mar. 17, 1999, now allowed, entitled SPOT-ON FORMULATIONS FOR COMBATTING PARASITES and Ser. No. 09/450,186, filed on Nov. 29, 1999, now pending, entitled DIRECT POUR-ON ANTIPARASITIC SKIN SOLUTION AND METHODS FOR TREATING, PREVENTING AND CONTROLLING MYASIS. Other spot-on or pour-on formulations are disclosed in copending application U.S. Ser. No. 10/052,597, filed on Jan. 17, 2002, now pending entitled INSECTICIDAL COMBINATION TO CONTROL MAMMAL FLEAS, IN PARTICULAR FLEAS ON CATS AND DOGS. The disclosure of these patent applications as well as the references cited therein and the references cited herein as well as the references cited in the references are expressly incorporated by reference.
An important area in veterinary science is the control of endo—and ectoparasites in warm-blooded animals, such as equine animals and domestic pets, such as cats and dogs. Infections of parasites, including cestodes and nematodes, commonly occur in animals such as horse, donkeys, mules, zebras, dogs and cats. Various classes anthelmintic agents have been developed in the art to control these infections; see, e.g., U.S. Pat. Nos. 3,993,682 and 4,032,655, which disclose phenylguanidines as anthelmintic agents. Further, the art recognizes that it is advantageous to administer combinations of two or more different classes of anthelmintic agents in order to improve the spectrum of activity; see, e.g., product disclosure for RM® Parasiticide-10, an anthelmintic paste comprising febantel and praziquantel.
Macrolide anthelmintic compounds are known in the art for treating endo—and ectoparasite infections in warm-blooded animals and birds. Compounds that belong to this class of agents include the avermectin and milbemycin series of compounds. These compounds are potent antiparasitic agents against a wide range of internal and external parasites. Avermectins and milbemycins share the same common 16-membered macrocyclic lactone ring; however, milbemycins do not possess the disaccharide substituent on the 13-position of the lactone ring. In addition to treating parasitic insects, avermectins and milbemycins are used to treat endoparasites, e.g., round worm infections, in warm-blooded animals.
The avermectin and milbemycin series of compounds either are natural products or are semi-synthetic derivatives. The natural product avermectins are disclosed in U.S. Pat. No. 4,310,519 to Albers-Schonberg, et al., and the 22,23-dihydro avermectin compounds are disclosed in Chabala, et al., U.S. Pat. No. 4,199,569. For a general discussion of avermectins, which include a discussion of their uses in humans and animals, see “Ivermectin and Abamectin,” W. C. Campbell, ed., Springer-Verlag, N.Y.(1989). Naturally occurring milbemycins are described in Aoki et al., U.S. Pat. No. 3,950,360 as well as in the various references cited in “The Merck Index” 12th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, N.J. (1996). Semisynthetic derivatives of these classes of compounds are well known in the art and are described, for example, in U.S. Pat. Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569, 5,055,596, 4,973,711, 4,978,677, and 4,920,148. All these documents are herein incorporated by reference.
Avermectins and milbemycins are ineffective against cestodes, such as tapeworms, which also are a common parasite in warm-blooded animals (see, U.S. Pat. No. 6,207,179). Moreover, echinococcus in companion animals is also very important due to the zoonotic potential to cause alveolar hydatid disease in humans. Of particular importance in the industry is the treatment of equine tapeworms, in general, and Anoplacephala perfoliata, in particular (see, e.g., U.S. Pat. No. 6,207,179 or U.S. Pat. No. 5,824,653). In order to treat cestode (and trematode) infections in warm-blooded animals, it is known, to administer 2-acyl-4-oxo-pyrazino-isoquinoline derivatives (see, e.g., U.S. Pat. No. 4,001,441, herein incorporated by reference), pyrantel-type compounds or morantel-type compounds to the animal. A compound of that is often used to treat cestode and trematode infections is praziquantel, which has the following structure: 
Various methods of formulating antiparasitic formulations are known in the art. These include oral formulations, baits, dietary supplements, powders, shampoos, etc. As mentioned above, often it is beneficial to administer a formulation that contains a combination of two or more anthelmintics, which possess different activity, in order to obtain a composition with a broad-spectrum of activity. Further, the combination allows the user to administer one formulation instead of two or more different formulations to the animal. Formulations which administer a combination of two or more anthelmintics are known in the art. These formulations may be in the form of solutions, suspensions, pastes, oral drenches or pour-on formulations (see, e.g., U.S. Pat. No. 6,165,987 to Harvey or U.S. Pat. No. 6,340,672 to Mihalik). For example, U.S. Pat. No. 4,468,390 to Kitano and U.S. Pat. No. 5,824,653 to Beuvry et al. describe oral anthelmintic compositions for treating nematode and cestode infections in animals, such as horses, that comprise an avermectin or a milbemycin and an isoquinoline compounds, such as praziquantel, to the animal. Similarly, U.S. Pat. No. 6,207,179 to Mihalik describes an oral anthelmintic paste formulations wherein the avermectin or milbemycin is dissolved in an on-aqueous liquid and pyrantel or morantel, compounds which are said in the art to be far less effective in treating tapeworm infections than praziquantel are suspended in the liquid. These prior patents do not describe a formulation wherein the both the praziquantel and the avermectin or milbemycin are dissolved in a solvent and administered to the animal topically. U.S. Pat. No. 6,165,987 describes oral or injectable anthelmintic formulations containing praziquantel and at least one avermectin or milbemycin dissolved in an ester or ester-like compounds, such as glycerol formal, benzyl alcohol and N-methyl-2-pyrrolidone, which may be liquids, pastes or drenches; the amount of praziquantel administered to the animal is always at a dose of more that 2.0 mg per kg of body weight.
Topical formulations for anthelmintic agents are also know in the art. These formulations include compositions for the localized topical applications of antiparasitical formulations, such as spot-on and pour-on solutions. An example of one of these formulations for fipronil is contained in copending application Ser. No. 08/933,016, herein incorporated by reference.
Spot-on formulations are well known techniques for topically delivering an antiparasitic agent to a limited area of the host. For example, U.S. Pat. No. 5,045,536 describes such formulations for ectoparasites. Moreover, it is generally known in the art to formulate avermectin and milbemycin derivatives as spot-on formulations. See, e.g. U.S. Pat. No. 5,045,536; EP 677,054; U.S. Pat. No. 5,733,877; U.S. Pat. No. 5,677,332; U.S. Pat. No. 5,556,868; and U.S. Pat. No. 5,723,488. However, as discussed in U.S. Pat. No. 5,045,536, a large number of solvent systems described in the art provide formulations for localized topical application which cause irritancy or toxicity to the host. Hence, there is a need in the art both for more effect and less irritant or toxic formulations as well as topical formulations which treat both nematode and cestode infections in animals.
U.S. Pat. No. 4,988,696 provides for a method of treating worms in cats by dermally applying praziquantel to the cat. U.S. Pat. No. 6,159,932 provides for topical endoparasiticidal compositions that comprise a macrocyclic lactone with a cyclic desipepside, optionally in the presence of praziquantel or epsiprantel. The inclusion of the praziquantel or epsiprantel is said to increase the action of the cyclic depsipeptides, compounds which are not contemplated by the present invention. U.S. Pat. No. 6,340,672 provides for pour-on parasiticidal formulation comprising, inter alia, praziquantel and avermectin; the formulations comprise a mixture of a pyrrolidone solvent and at least one solvent, such as diethylene glycol monobutyl ether or benzyl benzoate, which is said to form a solvent solution with active agents. The non-aqueous solvent employed in the present invention excludes the presence of solvent mixtures which can contain a pyrrolidone solvent.